A common ophthalmic condition is ocular hypertension. This term is used to describe the condition wherein the pressure inside the eye is higher than the normal range. Elevated intraocular pressure may occur, for example, due to (i) excessive aqueous fluid production, or (ii) blocking of the passages that normally allow fluid in to drain from the eyes. Generally with this condition there are no detectable changes in vision or damage to the structure of the eyes. The term “ocular hypertension” is also used to distinguish from the more serious eye condition, glaucoma.
Prolonged or severe ocular hypertension can sometimes lead to glaucoma, which causes damage to the optic nerve and loss of vision. Glaucoma is, in fact, one of the leading causes of blindness. The illness is most prevalent in people over the age of 40, particularly those who have a family history of glaucoma, and especially those who are very nearsighted or diabetic.
Although ocular hypertension and glaucoma cannot be cured, these conditions can be treated to reduce the risk of damage to the eye. The treatment regime usually begins with prescription eye drops and/or medicines to lower intraocular pressure. A number of alternative prescription eye drops are available, which contain different active ingredients and reduce the pressure in the eye by different mechanisms. For instance, the medicament may reduce the production of aqueous humour, or may increase the rate of fluid drainage from the eye.
Prostaglandin analogues are a common active ingredient of eye drops. They work by increasing the rate of fluid outflow from the anterior chamber of the eye. However, prostaglandins have a very low solubility in water and are generally also quite unstable. Therefore, in order to produce a commercially viable eye drop, the prostaglandin analogue must be both solubilised and stabilised so that the level of active ingredient remains constant over the lifetime of the medicament.
Poor solubility in water is not uncommon amongst commercially useful drugs. In fact, increasing the bioavailability of poorly soluble drug compounds is one of the greatest challenges the pharmaceutical industry faces. Cyclodextrins have been used as solubilisers and stabilisers of prostaglandins (EP 435 682 A2) and many other drugs (for a review, see Loftsson T. & Brewster M. E. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization, J. Pharm. Sci., 1996, 85(10), 1017-25). Also, a wide variety of surfactants, cosolvents and solubilisers have been developed to increase the water-solubility of drugs (see Samuel H. Yalkowski, Solubility and Solubilization in Aqueous Media, Am. Chem. Soc. 1999). However, the relative success of each of these approaches is variable and critically dependent on the particular drug and solvent system selected.
For instance, surfactants can be cationic, anionic, amphoteric and non-ionic, and whereas certain surfactants may be simply ineffective, others may actually enhance the chemical breakdown of a particular drug. Non-ionic surfactants such as polyethoxylated castor oils have been widely used as solubilisers, for instance, of the antibiotic Cyclosporin A (Ran Y. et al., Solubilization of Cyclosporin A. AAPS Pharm Sci Tech., 2001, 2(1), article 2), and as stabilising agents, such as for vitamin preparations (U.S. Pat. No. 4,075,333).
Polyethoxylated castor oils have also been used to create stable solutions for use in ophthalmic formulations containing, for example; ortho-(2,6-dichlorophenyl)-amino-phenylacetic acid for the control of eye inflammation (U.S. Pat. No. 4,960,799), vitamin A for the treatment of dry-eye syndrome (U.S. Pat. No. 5,185,372), and prostaglandin compositions for treating ocular hypertension and glaucoma (U.S. Pat. No. 5,631,287).
The solution stability of prostaglandins has been compared in both U.S. Pat. No. 5,631,287 and U.S. Pat. No. 5,849,792. In these studies it was shown that the use of polyethoxylated castor oils enhanced the stability of prostaglandins in ophthalmic formulations. In comparison, it was demonstrated that an alternative non-ionic surfactant, polysorbate 80, was unsuitable for use in a storage-stable solution. Particularly preferred polyethoxylated castor oils were Cremophor® EL and Alkamuls® EL-620, which were found to be far superior to polysorbate 80. However, polyethoxylated castor oils may not be tolerated by certain patients and accordingly, it has become imperative to find other stabilising and solubilising agents.
It has now been surprisingly found, however, that using carefully selected proportions, polysorbates are effective at stabilising prostaglandin solutions, and can provide enhanced levels of stability and freedom from impurities (such as breakdown products) in the final formulation, compared to use of polyethoxylated castor oils. The compositions of the invention therefore provide an important alternative to the use of formulations containing polyethoxylated castor oils, such as for use in ophthalmic medicaments, particularly for individuals whom are sensitive to the currently available prescription medications.